ENDOTHELIN(B) RECEPTOR-MEDIATED CONTRACTION OF HUMAN AND RAT PULMONARY RESISTANCE ARTERIES AND THE EFFECT OF PULMONARY-HYPERTENSION ON ENDOTHELIN RESPONSES IN THE RAT

We investigated the endothelin (ET) receptor subtypes that mediate vas oconstriction in human and rat pulmonary resistance arteries and the e ffect of pulmonary hypertension on endothelin (ET)-induced contractile responses in rat vessels. In human vessels, sarafotoxin S6c (SXS6c) w as more potent than ET-1, but its maximal contractile response was onl y 20-30% of that to ET-1. Responses to ET-1 were resistant to the ET(A ) antagonist FR 139317, and another, BMS 182874, inhibited responses o nly to high concentrations of ET-1. In all rat vessels, ET-1, ET-3, an d the ET(B) receptor agonist SXS6c showed the following order of poten cy: SXS6c = ET-3 > ET-1, and responses to SXS6c were inhibited by the ET(B) receptor antagonist BQ 788 (1 mu M). Maximal responses to ET-1 w ere greatest in chronic hypoxic (CH) pulmonary-hypertensive rats. In c ontrol rats, responses to ET-1 were unaffected by FR 139317 (1 mu M) a nd were potentiated by BMS 182874 (1 mu M) and by the mixed ET(A)/ET(B ) receptor antagonist bosentan (1 mu M). A combination of BMS 182874 ( 10 mu M) and the ET(B) receptor antagonist BQ 788 (1 mu M) had no effe ct on responses to ET-1. In the CH rats, responses to ET-1 were unaffe cted by FR 139317, BMS 182874, or bosentan. The results suggest the pr esence of an inhibitory ET(A) receptor in these vessels that may inhib it ET-1 activation of ET(B) receptors, and also suggest that the influ ence of this inhibitory ET(A) receptor is reduced in CH rat vessels. T he results indicate a role for ET(B) receptors in ET-1-mediated vasoco nstriction in both human and rat pulmonary resistance arteries.